1. Introduction
Since the early 1990s, an increasing number of counterfeit drugs in circulation can be observed [
1,
2]. Counterfeit medicines amount to an estimated USD 200 billion market annually, making it the largest identified fraud market globally [
3]. In 2022 there were 6615 pharmaceutical crime incidents, corresponding to an increase of 10% compared to 2021 [
4]. The World Health Organization (WHO) reports that 10% of the global pharmaceutical trade [
5] and as much as 25% in developing countries [
6] involves counterfeit drugs. Some sources even state that in in parts of Africa and Asia, this figure exceeds 50% [
4,
7]. In 2021 Interpol’s worldwide operation discovered more than 3 million counterfeit medicines and medical devices in the UK supply chain worth GBP 9 million [
8]. Another operation by Europol seized more than 25 million units of medicines with a value of around EUR 63 million [
9]. Already 10 years ago, piracy and counterfeiting cost US businesses more than USD 200 billion annually [
10] and causes a total loss of life of between 100,000 and 1,000,000 people worldwide per year [
11]. Highly prone to counterfeiting are anti-malaria drugs such as artesunate, where 30 to 50% of all packets bought in southeast Asia were fake [
12,
13]. Thus, the counterfeiting of pharmaceutical products is a global challenge [
5]. According to the WHO definition, a counterfeit medicine is “A medicine that is deliberately and fraudulently mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredients or with fake packaging” [
14]. This poses a growing threat to public health as they can deliver hazardous treatment or even cause death [
15].
Counterfeit drugs are hard to detect. Possible techniques for detection are visual features such as packaging, labeling, including spelling mistakes and product security features, and physical (surface discoloration, disintegration, dissolution), or chemical analysis (spectroscopy, chromatography, spectrometry) [
16,
17,
18]. This emphasizes the need for the development of advanced technologies for improved anti-counterfeiting measures for drugs, which should be hard to duplicate, easy to prepare, high-throughput, convenient to recognize, inexpensive [
19,
20], and legally accepted. However, the FDA supports a wide range of anti-counterfeiting techniques and detection methods [
14,
21].
Several anti-counterfeiting technologies [
22] include: tamper-resistant packaging [
23,
24,
25], track and trace technology [
26,
27], and product authentication. These can either be covert [
16] (such as embedded images, digital watermarks) or overt features [
15,
19,
28]. Even features of a forensic nature, where chemical or biological taggants are introduced into a tablet, are already in development [
29,
30,
31,
32].
However, the forensic technique requires licensed technologies for read-out and is thus expensive and unlikely to be available to authorities and the public. The currently most employed anti-counterfeiting measures are data carriers, such as RFID (radio-frequency identification) tags [
33,
34], or 2D identification methods [
19,
35,
36]. For example, Pfizer uses RFID tags for its Viagra
® product, GlaxoSmithKline for Trizivir
®, and Purdue Pharma labels its Oxycodone product with an RFID tag [
33]. Several drawbacks of these anti-counterfeiting measures are that they need to be varied frequently, but patients and the authorities would need information to know which features to look for. Furthermore, covert, or overt features on the packaging would be useless if the product is repackaged.
Therefore, the implementation of anti-counterfeiting measures directly onto the tablet is a necessity. If possible, even a combination of hidden anti-counterfeiting measures and easily recognizable visual features would be the goal.
Herein, we present a novel approach to anti-counterfeiting techniques specifically utilizing the advantages of 3D screen printing (Laxxon Medical GmbH, Jena, Germany, US Patent 20140065194). By employing the 3D screen printing technique where an aqueous dispersion of excipients and API are printed through a screen mesh onto a substrate, thousands of strongly defined tablets can be printed per screen simultaneously. The geometry is defined by the layout of an impermeable emulsion which blocks certain areas on the mesh. After one printing cycle, the deposited layer is dried. The next layer is printed precisely on top of the previous one after lifting the screen by thickness of the dried layer. Subsequently, a three-dimensional geometry is constructed [
37,
38,
39].
Laxxon Medical Corp. (New York, NY, USA) already developed a proof-of-concept work with 3DSP (SPID
®-Technology, Stetten, Switzerland) having shown its anticounterfeiting potential by printing QR codes directly on tablets as small as r = 5 mm during and as integral part of the manufacturing process [
39].
Since 3D screen printing with SPID® technology is a controlled and licensed manufacturing technology that is not generally available, it is impossible to mimic these features in an uncontrolled environment and without extensive technological and development resources. Therefore, this technology does not lend itself to easy duplication.
In addition to the proof-of-concept work on overt anti-counterfeiting measures such as QR-codes imprinted to the surface of a tablet [
39], 3DSP offers a new level of anti-counterfeiting strategies, that is, the implementation of covert features within oral dosage forms, which are impossible to counterfeit using conventional techniques. In this paper we present a proof-of-concept study for embedding a covert cross structure into a tablet. With only two screen and paste changes, a structure can be integrated into a tablet which exhibits a distinct pattern upon the breakage of the tablet in either the middle or slightly off-center. Additionally, the only difference in the paste compared to the overall tablet material is the addition of food coloring, meaning only a subtle change in API content due to the addition of food coloring and no strongly irregular API distribution in the tablet. This means that no alteration in the biopharmaceutical performance would be expected compared to a homogenous tablet without the embedded cross.
2. Materials and Methods
2.1. Chemicals
Materials used are listed along with their providers in brackets: Paracetamol (acetaminophen; Caelo (Hilden, Germany), Avicel PH-105 (Dupont, Wilmington, DE, USA), glycerol (AppliChem, Darmstadt, Germany), calcium sulfate (Honeywell, Morristown, NJ, USA), talc (Carlo ERBA, Germany), silfar (Wacker Chemie, Germany), hydroxypropyl cellulose (Klucel® LF, Ashland, Wilmington, DE, USA ) and Polyplasdone Ultra 10 (Ashland, Covington, KY, USA), pharmatose 450 M (DFE Parma, Goch, Germany), blue dispersible color (TopMill® blue 260.36) was kindly provided by Biogrund (Huenstetten, Germany). Milli-Q water (18.2 MΩ cm) was used for all formulations and solutions.
2.2. Preparation of Printing Pastes
All pastes (1 and 2, see
Table 1 and
Table 2) were mixed with a vacuum dissolver planetary mixer HRV-S 2DP from Herbst Maschinenfabrik GmbH (Buxtehude, Germany) with 3 agitator tools in a 2-L glass container.
P1, used to build the tablet body, was generated at room temperature according to the composition in
Table 1. Briefly, a 10 wt% gel of Klucel LF Pharma was prepared. The appropriate amount of binder gel (
Table 1, Klucel
® LF Pharma) was then added into the 2-L glass container of the planetary mixer. In the next step, all other ingredients were added into the glass container. Mixing was performed for 20 min at 1000 rpm under 70 mbar vacuum.
P2 for the blue cross was formulated according to the composition in
Table 2 under room temperature conditions. Its preparation followed the path outlined for P1 applying the same mixing conditions.
2.3. Rheology Measurements
Rheology measurements were performed on a Kinexus Rheometer (Netzsch, Selb, Germany), equipped with a plate-plate geometry and a passive solvent trap at 25 °C. A 500 µm gap was selected. In the 3-step shear rate test, shear rates of 0.1 s−1 (for 1.5 min), 100 s−1 (for 0.5 min) and 0.1 s−1 (for 10 min), were applied. The amplitude sweep was conducted at 1 Hz, and the frequency sweep at 0.05% strain.
2.4. 3D Screen Printing of Tablets
Tablets were fabricated on the prototype inline unit EX301i from Exentis Group AG (Stetten, Switzerland). Their lateral dimensions were determined by the used screen layouts (for example, see
Figure 1). Machine preparation for the printing process included mounting and alignment of the screen (Pröll Services GmbH, Hildesheim, Germany) and the squeegees, as well as the set-up of the software SIMPLEX EKRA HMI 2010 (Esp021-104-2021-09-08-0). Printer settings used were as follows: flooding squeegee speed 100 mm s
–1, printing squeegee speed 65 mm s
–1, off-contact distance 2 mm, height increment for screen elevation 60 µm, dryer temperature 80 °C (convection dryer), and speed of conveyor belt under convection dryer 2 m min
–1. Using these settings, 55 layers were printed. To enable a colored cross in the middle of the tablets, the two pastes and the two screens needed to be changed during the printing process. Firstly, Paste 1 was used for 25 layers with Screen 1 (
Figure 1), then Paste 2 was utilized to print the colored cross for 5 layers on top with Screen 2 (
Figure 1). Afterwards 25 layers of Paste 1 were printed to finish the tablets using Screen 1.
Tablets were printed on tempered glass plates (300 × 300 × 5 mm3) with a satin-finished surface. Upon completion of the printing process, tablets were left on the plates for overnight air-drying at room temperature before they could be readily displaced by applying tangential mechanical force with a razor blade.
The inline printer was equipped with 10 glass plates (capacity: n = 13). For demonstration reasons, one printing plate was removed during the printing step after printing the colored cross to visualize the inside geometry of the tablet.
2.5. Tablet Hardness and Friability Testing
Resistance to crushing was determined according to Ph. Eur. 2.9.8 (10). Five tablets of each size and shape were tested with a Pharmatest PTB 511E (Pharma Test Apparatebau AG, Hainburg, Germany). Friability was assessed according to Ph. Eur. 2.9.7 (10). Approximately 6.5 g tablets of each size and shape were dedusted with compressed air, weighed, placed in the friability tester Pharmatest PTF 100 (Pharma Test Apparatebau AG, Hainburg, Germany) and rotated 100 times at a constant speed of 25 rpm. Thereafter, they were removed, dedusted and weighed.
2.6. Mass Uniformity
The weight variation test was used to assess mass uniformity. The individual weight of 20 tablets from each formulation/geometry was determined, and the average/variation was calculated.
2.7. Dimension Uniformity
Dimension uniformity was quantified with the dimension variation test. The 3 dimensions of 20 tablets from each formulation/geometry were measured with a Digimatic Caliper CD-15APX (certified) and the average/variation was calculated. Mean and standard deviations of the surface area SA, volume V, surface-area-to-volume-ratio SA/V and density ρ of the tablets were calculated based on these measured values.
2.8. Disintegration Testing
Disintegration was tested according to Ph. Eur. 2.9.1. Six tablets of each size and shape were applied to a Pharmatest Auto1EZ (Pharma Test Apparatebau AG, Hainburg, Germany), an automatic disintegration time tester using discs and demineralized water (750 mL, 37 °C) as medium. Data are reported as average ± standard deviation.
2.9. Dissolution Testing
Dissolution experiments were performed according to the USP monograph “Acetaminophen tablets” section dissolution of the US Pharmacopeia. An Agilent® dissolution paddle apparatus equipped with an Agilent sampling station was used. Testing was performed using 900 mL phosphate buffer, pH = 1.2 at 37.0 ± 0.5 °C, with stirring at 50 rpm. Sink conditions were used.
Analysis (n = 6) was performed using an Agilent 1260 Infinity II HPLC, equipped with a Kromasil C-18 250 × 4.6 mm 5 µm column (Nouryon AB, Göteborg, Sweden) at a temperature of 35 °C, 20 µL injection volume and measured at an absorption of λ = 243.
A calibration curve in the range of 6.25–400 µg/mL Paracetamol was made, which correlated with R = 0.9999.
4. Conclusions
In conclusion, it could be shown that 3DSP allows for the manufacturing of tablets with a distinct inner architecture, namely the integration of a colored cross at a large scale. This feature offers anti-counterfeiting properties. In a continuous process with only 2 stops change the screen and paste, several thousand tablets were manufactured. However, if scaled up, 3DSP can produce up to 200,000 tablets per hour depending on the type of screen and machine (e.g., inline, two printing stations) used.
As a proof-of-concept, a colored paste was used for the embedded cross. Interestingly, due to the high flexibility regarding processable materials, one can contemplate the use of materials with distinct features such as micro- or nanoparticles, [
26,
47] DNA-strands [
48], or ultraviolet inks [
49]. Due to the gentleness of the process, even delicate materials are processable. The drying temperature can also be tuned to lower values at the expense of the cycle time. The combination of several anti-counterfeiting measures would tremendously enhance the safety and protection of the dosage form. Here, 3DSP offers the possibility of a combination of covert (such as the embedded cross presented herein) and overt (e.g., a QR-code) [
39] features in a single process with minor intermediate steps.
Even changes in an established anti-counterfeiting feature, e.g., the embedded cross, could easily be applied by simply changing the geometry of the second screen to, for instance, a star or line pattern, or by changing the type of paste (e.g., added security inks [
50,
51]) to complicate the counterfeiting of the dosage form. There are no limits to the layout of the embedded feature, since very fine patterns can also be resolved using 3DSP [
39].
This innovative approach demonstrates the power of 3D screen printing to implement novel and innovative anticounterfeiting measures into the manufacturing of solid oral dosage forms. The method’s simplicity and adaptability to other formulations makes it a potential solution to enhance drug security, pushing the frontiers in the fight against counterfeit drugs in favor of patients and even the stakeholders involved in the pharmaceutical industry.